Structural Basis of DEPTOR to Recognize Phosphatidic Acid Using its Tandem DEP Domains |
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| Affiliation: | 1. School of Medicine, Sun Yat-Sen University, Guangzhou 510275, China;2. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Guangzhou 510275, China;3. Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China;1. The Donnelly Centre, University of Toronto, Toronto, Canada;2. Department of Molecular Genetics, University of Toronto, Toronto, Canada;3. Département de Biochimie, Université de Montréal, Montréal, Canada;1. Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany;2. Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany;3. Department of Chemistry, Center for Structural Biology, Vanderbilt University, 465 21st Ave South, BIOSCI/MRBIII, Nashville, TN 37235, USA;4. Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany;1. Biophysics, Department of Chemistry, Macromolecular Engineering and Science, and Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA;2. Condensed Matter Theory Group, Materials Theory Division, Department of Physics and Astronomy, Uppsala University, Box 516, SE-75120 Uppsala, Sweden;3. Ben-May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA;4. Applied Materials Physics, Department of Materials Science and Engineering, Royal Institute of Technology (KTH) SE-10044 Stockholm, Sweden;1. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;2. Laboratoire d’Enzymologie et de Biochimie Structurales, Centre de Recherche de Gif, CNRS, 91198 Gif-sur-Yvette, France;1. Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA;2. School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA;3. Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA;4. Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI, USA;5. Morgridge Institute for Research, Madison, WI, USA;6. Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI, USA;1. Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, 455 Main Street, Cambridge, MA 02142, USA;2. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA;3. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA;4. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA;5. Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, 01605, USA;6. Howard Hughes Medical Institute, Janelia Research Campus, 19700 Helix Drive, Ashburn, VA 20147, USA |
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| Abstract: | DEP domain containing mTOR-interacting protein (DEPTOR) plays pivotal roles in regulating metabolism, growth, autophagy and apoptosis by functions as an endogenous inhibitor of mTOR signaling pathway. Activated by phosphatidic acid, a second messenger in mTOR signaling, DEPTOR dissociates from mTORC1 complex with unknown mechanism. Here, we present a 1.5 Å resolution crystal structure, which shows that the N-terminal two tandem DEP domains of hDEPTOR fold into a dumbbell-shaped structure, protruding the characteristic β-hairpin arms of DEP domains on each side. An 18 amino acids DDEX motif at the end of DEP2 interacts with DEP1 and stabilizes the structure. Biochemical studies showed that the tandem DEP domains directly interact with phosphatidic acid using two distinct positively charged patches. These results provide insights into mTOR activation upon phosphatidic acid stimulation. |
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| Keywords: | DEPDC6 DDEX motif mTOR anionic lipid crystal structure DEPTOR" },{" #name" :" keyword" ," $" :{" id" :" k0035" }," $$" :[{" #name" :" text" ," _" :" DEP domain containing mTOR, interacting protein PA" },{" #name" :" keyword" ," $" :{" id" :" k0045" }," $$" :[{" #name" :" text" ," _" :" phosphatidic acid DEPDC6" },{" #name" :" keyword" ," $" :{" id" :" k0055" }," $$" :[{" #name" :" text" ," _" :" DEP-domain containing protein 6 DEP" },{" #name" :" keyword" ," $" :{" id" :" k0065" }," $$" :[{" #name" :" text" ," _" :" Dishevelled, Egl-10, Pleckstrin PDZ" },{" #name" :" keyword" ," $" :{" id" :" k0075" }," $$" :[{" #name" :" text" ," _" :" Postsynaptic density 95, Discs large, Zonulaoccludens-1 RGS9" },{" #name" :" keyword" ," $" :{" id" :" k0085" }," $$" :[{" #name" :" text" ," _" :" the Regulator of G-protein signaling 9 Epac2" },{" #name" :" keyword" ," $" :{" id" :" k0095" }," $$" :[{" #name" :" text" ," _" :" exchange protein directly activated by cAMP P-Rex1" },{" #name" :" keyword" ," $" :{" id" :" k0105" }," $$" :[{" #name" :" text" ," _" :" Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchanger 1 protein Sst2" },{" #name" :" keyword" ," $" :{" id" :" k0115" }," $$" :[{" #name" :" text" ," _" :" the yeast homologue of the RGS family DDEX" },{" #name" :" keyword" ," $" :{" id" :" k0125" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" underline" ," _" :" D" },{" #name" :" __text__" ," _" :" EPTOR-" },{" #name" :" underline" ," _" :" D" },{" #name" :" __text__" ," _" :" EP2 " },{" #name" :" underline" ," _" :" ex" },{" #name" :" __text__" ," _" :" tension LPA" },{" #name" :" keyword" ," $" :{" id" :" k0135" }," $$" :[{" #name" :" text" ," _" :" lysophosphatidic acid LPC" },{" #name" :" keyword" ," $" :{" id" :" k0145" }," $$" :[{" #name" :" text" ," _" :" lysophosphatidylcholine PI" },{" #name" :" keyword" ," $" :{" id" :" k0155" }," $$" :[{" #name" :" text" ," _" :" phosphatidylinositol PIXPn" },{" #name" :" keyword" ," $" :{" id" :" k0165" }," $$" :[{" #name" :" text" ," _" :" phosphatidylinositol X phosphaten PE" },{" #name" :" keyword" ," $" :{" id" :" k0175" }," $$" :[{" #name" :" text" ," _" :" phosphatidyl-ethanolamine PC" },{" #name" :" keyword" ," $" :{" id" :" k0185" }," $$" :[{" #name" :" text" ," _" :" phosphatidylcholine S1P" },{" #name" :" keyword" ," $" :{" id" :" k0195" }," $$" :[{" #name" :" text" ," _" :" sphingosine-1-phosphate PS" },{" #name" :" keyword" ," $" :{" id" :" k0205" }," $$" :[{" #name" :" text" ," _" :" phosphatidylserine |
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